Multi-layered transdermal system with triazine uv absorber

ABSTRACT

The UV-stable solid transdermal therapeutic system (TTS) with UV absorber for photosensitive active pharmaceutical ingredients has a backing layer ( 1 ), at least one active ingredient-containing matrix ( 2 ), and a detachable protective film ( 3 ). Optionally an adhesive layer ( 4 ) and a separating layer ( 5 ) are introduced between the backing layer ( 1 ) and the at least one active ingredient-containing matrix ( 2 ). At least one hydroxyphenyltriazine compound acting as UV absorber is embedded in the backing layer ( 1 ), in the active it matrix ( 2 ), or in the adhesive layer ( 4 ). The TTS according to the invention achieves high stability at low concentrations of UV absorber, preferably 0.5 to 3% (m/m), so as to reduce or avoid skin irritation.

CROSS-REFERENCE

The invention described and claimed hereinbelow is also described inU.S. Provisional Patent Application 60/676,788, filed May 2, 2005, andalso in European Patent Application No. 05009579.3, also filed May 2,2005. The aforesaid US Provisional Patent Application, whose subjectmatter is incorporated here by reference, provides the basis for a claimof priority of invention under 35 U.S.C. 119 (e).

BACKGROUND OF THE INVENTION

The invention is a solid transdermal therapeutic system with UVabsorber. The UV-stable transdermal therapeutic system (TTS) isparticularly designed for photosensitive active pharmaceuticalingredients. It comprises a backing layer 1, of at least one activeingredient-containing matrix 2, and of a detachable protective film 3.However an adhesive layer 4 and a separating layer 5 can optionally beintroduced between the backing layer 1 and the activeingredient-containing matrix 2. At least one hydroxyphenyltriazineacting as UV absorber can be embedded in the backing layer 1, in theactive ingredient-containing matrix 2, or in the adhesive layer 4.

Transdermal therapeutic systems, which contain a gestagen and/or anestrogen, are suitable for controlling fertility.

Attempts to employ photosensitive active ingredients, which absorb UV-Aand UV-B rays, customarily used in sun creams, are known, as describedby Briscart & Plaizier-Vercammen (Proc. 2^(nd) World Meeting onPharmaceutics, Biopharmaceutics and Pharmaceutical Technology, APGI/APV,1998, 1231-1232).

The patent literature further discloses the protection of transdermaltherapeutic systems (TTS) provided with photosensitive activeingredients by visually conspicuous aluminized or lacquered coveringfilms as backing layers of the TTS.

WO-A1-00/56289 describes a method for protecting therapeuticpreparations, systems or their constituents, the intention being toachieve in each case specific protection from degradation by harmfulfactors, such as atmospheric oxygen, water, and/or light.Photo-protective substances, which absorb or reflect electromagneticwaves, are used, employing respectively absorbents or reflectants whoseabsorption or reflection spectrum covers the wave-length rangeresponsible for the instability of the photosensitive substance or itsconstituents. Colored plastic films are used, inter alia, in this caseas covering film, indicated by example of the 1,4-dihydopyridinederivative lacidipine.

The coloring of highly flexible plastic films proves to be difficult anddoes not provide reliable photo-protection owing to the frequentlyoccurring fissures in the colored layer of the plastic film.

WO-A2-02/34200 further discloses transdermal therapeutic systems (TTS),which consist of an active ingredient-containing polymer matrix and of abacking layer. The polymer matrix and the backing layer are firmlyconnected or form a laminate. Both the polymer matrix and the backinglayer comprise a colorless system, which absorbs in the UV range but hasno intrinsic pharmacological effect. EP-A1-1452173 describes transdermaltherapeutic systems, which consist of a backing layer, of at least oneactive ingredient-containing matrix and optionally of a detachable filmand comprises a UV absorber. At least one UV absorber-containingadhesive layer is provided between the backing layer and the activeingredient-containing matrix furthest away from the surface of the skin.In addition, at least one separating layer, which is impermeable toactive ingredient and impermeable to the UV absorber, is present betweenthe adhesive layer containing the UV absorber and the activeingredient-containing matrix, which is furthest away from the surface ofthe skin. The UV absorber can be p-aminobenzoic acid, an aminobenzoicacid derivative, preferably 2-ethylhexyl 4-dimethyl-amino-benzoateand/or polyethoxyethyl 4-bis-(polyethoxyl)amino-benzoate, cinnamic acid,a cinnamic acid derivative, preferably isoamyl 4-methoxycinnamate or2-ethylhexyl 4-methoxycinnamate, 3-benzylidenebornan-2-one, abenzylidene bornan-2-one derivative, preferably3-(4′-methylbenzylindenebornan-2-one,3-(4-sulphone)-benzylidenebornan-2-one, or3-(4′-trimethylammonium)-benzylidenebornan-2-one methylsulphate,salicylic acid derivative, preferably 4-isopropylbenzyl salicylate,2-ethylhexyl salicylate, or 3,3,3-trimethylcyclohexyl salicylate, abenzotriazole, preferably 2-(5-chloro-2H-benzotriazol-2-yl)-6-(1,1-dimethylethyl)-4-methylphenol, 3-imidazol-4-yl-acrylic acid,3-imidazol-4-yl-3-imidazol-4-yl-acrylic ester, 2-phenylenebenzimidazole-5-sulphonic acid, or its K, Na and triethanolamine (=TEA)salt, 2-cyano-3,3-diphenylacrylic acid,terephthaloylidene-dicamphorsulphonic acid,butylmethoxy-dibenzoylmethane, benzophenone, or a benzophenonederivative, preferably benzophenone-3 or benzophenone-4.

The known solutions have the disadvantage

-   -   that the protective effect produced by the added UV absorber for        the active ingredient is incomplete,    -   that owing to the incomplete protective effect in some cases        higher concentrations of UV absorbers must be employed, which        may have adverse effects on the compatibility of the TTS with        skin.

SUMMARY OF THE INVENTION

It is therefore an object of the invention to provide a pharmaceuticalpreparation of the above-described kind with a UV absorber, which isprovided with a photosensitive active ingredient, which is to betransdermally administered, and which ensures an increased protectiveeffect for the active ingredient while using a minimum UV absorberconcentration, so that the aforementioned disadvantages are avoided.

This object is achieved according to the invention by a solidtransdermal therapeutic system (TTS) with a UV absorber, wherein theUV-stable TTS comprises a sequence of at least three layers, namely abacking layer 1, at least one active ingredient-containing matrix 2, anda detachable protective film 3. Optionally an adhesive layer 4 and aseparating layer 5 can be introduced between the backing layer 1 and theat least one active ingredient-containing matrix 2. In the transdermaltherapeutic system according to the invention the UV absorber comprisesat least one hydroxyphenyltriazine compound and the UV absorber isembedded in the backing layer 1, in the active ingredient-containingmatrix 2, or in the adhesive layer 4.

BRIEF DESCRIPTION OF THE DRAWING

The objects, features and advantages of the invention will now beillustrated in more detail with the aid of the following detaileddescription and examples of the invention, with reference to theaccompanying figures, in which:

FIG. 1 is a graphical illustration showing the percentage ofphotosensitive active ingredient remaining in a transdermal therapeuticsystem according to the invention with photo-protective features and thepercentage of photosensitive active ingredient remaining in acomparative transdermal therapeutic system; and

FIGS. 2 to 4 are respective diagrammatic cross-sectional views throughvarious embodiments of the transdermal therapeutic systems according tothe invention.

DETAILED DESCRIPTION OF THE INVENTION

In a preferred embodiment according to the invention the UV absorber is2,4-bis-([4-(2′-ethylhexyloxy)-2-hydroxy]phenyl)-6-(4-methoxyphenyl)-(1,3,5)-triazine.

In various embodiments of the transdermal therapeutic systems accordingthe weight per unit area of the matrix 2 is from 30 to 150 g/m². In thisconnection, a weight per unit area of from 50 to 120 g/m² is preferred,and of 100 g/m² is particularly preferred.

Similarly in various embodiments of the solid transdermal therapeuticsystem according to the invention the weight per unit area of theadhesive layer 4 is from 5 to 50 g/m². In this connection, a weight perunit area of from 20 to 30 g/m² is preferred.

The UV absorber can be present according to the invention in theadhesive layer 4 in a concentration of from 0.5 to 5% (m/m) in dissolvedform. In this connection, a concentration of from 1.0 to 4.0% ispreferred, and of from 1.5 to 3.0% is particularly preferred.

Furthermore the matrix 2 and/or the adhesive layer 4 in the solidtransdermal therapeutic system can be designed according to theinvention to be self-adhesive and can consist substantially of polymers,which are selected from the group consisting of polyisobutylene,polybutene, polyacrylate, polydimethylsiloxane, styrene-isoprene blockpolymer and polyisoprene.

Preferred embodiments of the solid transdermal therapeutic systemsaccording to the invention have a separating layer thickness of from 4to 23 μm. In this connection, a layer thickness of from 4 to 10 μm ispreferred.

In the solid transdermal therapeutic systems according to the inventionthe separating layer 5 is preferably impermeable to the activeingredient and impermeable to the UV absorber.

In preferred embodiments of the invention the separating layer 5 canconsist of a barrier polymer. Preference is given in this connection topolyethylene terephthalate, polyacrylonitrile, polyvinyl chloride,polyvinylidene chloride, or its copolymers or co-laminates.

In preferred embodiments of the solid transdermal therapeutic systemaccording to the invention the backing layer 1 is permeable to activeingredient and consists of polypropylene, of polyethylene, ofpolyurethane, of ethylene-vinyl acetate copolymer, or of a multilayercomposite of these materials with one another or with other materials.

The UV absorber(s) in the solid transdermal therapeutic system accordingto the invention can be colorless or yellowish.

It is furthermore possible for the solid transdermal therapeutic systemaccording to the invention to be transparent or slightly opaque.

The active ingredient in the solid transdermal therapeutic systemaccording to the invention can be at least one hormone.

The active pharmaceutical ingredient according to the invention can be aprogestogen, preferably gestodene or levonorgestrol. Furthermore anestrogen, preferably ethinyl estradiol, can be added to the progestogenin the solid transdermal therapeutic system according to the invention.

According to the invention the solid transdermal therapeutic system canalso be used to control fertility.

It is also possible according to the invention for the solid transdermaltherapeutic system to be equipped without a membrane controlling activeingredient release.

The transdermal therapeutic system according to the invention has thefollowing advantages compared with conventional systems withphotosensitive active ingredient content.

-   -   The protective effect provided by the hydroxyphenyltriazine        compounds acting as UV absorber is enhanced.    -   The concentration of the hydroxyphenyitriazine compounds acting        as UV absorber, which is necessary to achieve a protective        effect is reduced.    -   It is thus possible in particular to avoid or reduce the risk of        possible skin irritation.

The invention is further illustrated and explained by the followingexamples.

EXAMPLE 1

Two formulations (1 and 2) of a photosensitive active ingredient fromthe progestogens were prepared. Formulation 2 comprises an adhesivelayer 4 and a separating layer 5, and the adhesive layer comprises 2.5%by weight of a UV-absorbing substance from the hydroxyphenyltriazinecompounds. Formulation 1 has no adhesive layer and no separating layer.Formulation 1 serves as comparative formulation. Both formulationscomprise an active ingredient-containing matrix 2 with a photosensitiveprogestogen and are equipped with a backing layer 1 of polyethylene,resulting in a TTS in each case. Formulation 2 has the followingcomposition:

-   -   1. Active ingredient-containing matrix:        -   1.9% progestogen        -   98.1% polyisobutylene-based adhesive;    -   2. Adhesive layer:        -   3% Tinosorb® S        -   97% polyisobutylene-based adhesive.            Tinosorb® S (from Ciba, Lampertheim) is a UV absorber of the            hydroxyphenyltriazine class.

To investigate the photo-protective effect, both formulations wereirradiated with light having a UV spectrum of 300-800 nm for a period ofup to 34 h. The radiation source used was a xenon lamp. A filter system(type: Suprax® filter) was placed between the radiation source and thesamples to be irradiated in order to simulate irradiation underrealistic conditions of use of the TTS. The active ingredient content inthe TTS after irradiation was then determined.

FIG. 1 reveals that the TTS of formulation 2, which comprised anadhesive layer with UV-absorbing substance and a separating layer, stillcomprised about 95% of the originally employed amount of thephotosensitive active ingredient after irradiation for 34 h, whereas theTTS of formulation 1 comprised only about 3% of the originally employedamount of the photosensitive active ingredient after irradiation.

The system according to the invention has improved protection from thesun under realistic conditions-of-use, since the UV-protective effect ofthe system according to the invention (formulation 2) was considerablygreater than that of the comparative system (formulation 1).

EXAMPLE 2

The formulations of example 2 have a photosensitive active ingredientfrom the progestogens, and in each case an adhesive layer and separatinglayer. The separating layer in each of these formulations consists ofpolyethylene terephthalate (Hostaphan®¹ from Mitsubishi Polyester,Wiesbaden). Each formulation has the following composition:

-   1. Active ingredient-containing matrix    -   1.9% progestogen    -   98.1% polyisobutylene-based adhesive;-   2. Adhesive layer 1 and 2:    -   2.5% Tinosorb® S    -   97.5% polyacrylate-based adhesive.

EXAMPLE 3

The formulations of example 3 have a photosensitive active ingredientfrom the progestogens, and in each case two adhesive layers andseparating layers. The separating layers in each case consist ofpolyethylene terephthalate (Hostaphan®¹ from Mitsubishi Polyester,Wiesbaden). These formulations each have the following composition:

-   1. Active ingredient-containing matrix:    -   1.9% progestogen    -   98.1% polyisobutylene-based adhesive;-   2. Adhesive layer 1 and 2:    -   3% Tinuvin®400    -   97% polyacrylate-based adhesive.        Tinuvin®400 (from CIBA, Lampertheim) is a UV absorber of the        hydroxyphenyltriazine class.

EXAMPLE 4 TO 12

The formulations of example 4 have a photosensitive active ingredientfrom the progestogens, and in each case at least one adhesive layer andseparating layer. In these formulations in which the activeingredient-containing matrix is embodied analogous to examples 1 to 3and the adhesive layer comprises a poly-isobutylene-based adhesive andhas the compositions mentioned below.

Composition of the adhesive Example layer 4 5 6 7 8 9 10 11 12Tinosorb ® S [%] 2 2 2 3 3 3 4 4 4 Polyisobutylene-based 98 98 98 97 9797 96 96 96 adhesive [%] Weight per unit area [g/m²] 20 30 50 20 30 5020 30 50

EXAMPLE 13 TO 21

The formulations of examples 13 to 21 have a photosensitive activeingredient from the progestogens, and in each case at least one adhesivelayer and separating layer. The active ingredient-containing matrix isembodied analogously to examples 1 to 3, and the adhesive layercomprises a polyacrylate-based adhesive and has the compositionsmentioned below.

Composition of the Example adhesive layer 13 14 15 16 17 18 19 20 21Tinosorb ® S [%] 2 2 2 3 3 3 4 4 4 Polyacrylate-based 98 98 98 97 97 9796 96 96 adhesive [%] Weight per unit area [g/m²] 20 30 50 20 30 50 2030 50

While the invention has been illustrated and described as embodied in asolid transdermal therapeutic system with UV absorber, it is notintended to be limited to the details shown, since various modificationsand changes may be made without departing in any way from the spirit ofthe present invention.

Without further analysis, the foregoing will so fully reveal the gist ofthe present invention that others can, by applying current knowledge,readily adapt it for various applications without omitting featuresthat, from the standpoint of prior art, fairly constitute essentialcharacteristics of the generic or specific aspects of this invention.

What is claimed is new and is set forth in the following appendedclaims: 1.-24. (canceled)
 25. A solid transdermal therapeutic system(TTS) with a UV absorber, said solid transdermal therapeutic systemcomprising a sequence of at least five layers; wherein said at leastfive layers comprise a backing layer (1), an adhesive layer (4), aseparating layer (5), at least one active ingredient-containing matrix(2), and a detachable protective film (3); wherein the adhesive layer(4) is between the backing layer (1) and the separating layer (5), theseparating layer (5) is between the adhesive layer (4) and the at leastone active ingredient-containing matrix (2), and the at least one activeingredient-containing matrix (2) is between the separating layer (5) andthe detachable protective film (3); wherein said UV absorber consists of2,4-bis-([4-(2′-ethylhexyloxy)-2-hydroxy]phenyl)-6-(4-methoxyphenyl)-(1,3,5)-triazineas the sole UV absorber in the system, said UV absorber is present in aconcentration of from 0.5 to 4.0% (m/m) in dissolved form in theadhesive layer and said UV absorber is also optionally present in thebacking layer (1); and wherein the solid transdermal therapeutic systemis transparent.
 26. The solid transdermal therapeutic system as definedin claim 25, wherein the at least one active ingredient-containingmatrix (2) has a weight per unit area of from 30 to 150 g/m².
 27. Thesolid transdermal therapeutic system as defined in claim 26, wherein theweight per unit area of the at least one active ingredient-containingmatrix (2) is from 50 to 120 g/m².
 28. The solid transdermal therapeuticsystem as defined in claim 25, wherein the adhesive layer (4) has aweight per unit area of from 5 to 50 g/m².
 29. The solid transdermaltherapeutic system as defined in claim 28, wherein the weight per unitarea of the adhesive layer (4) is from 20 to 30 g/m².
 30. The solidtransdermal therapeutic system as defined in claim 25, wherein saidconcentration of said UV absorber is from 1.0 to 2.0% (m/m) in dissolvedform in the adhesive layer (4).
 31. The solid transdermal therapeuticsystem as defined in claim 25, wherein the at least one activeingredient-containing matrix (2) and the adhesive layer (4) areself-adhesive and comprise at least one polymer; wherein said at leastone polymer is selected from the group consisting of polyisobutylene,polybutene, polyacrylate, polydimethylsiloxane, styrene-isoprene blockpolymers and polyisoprene.
 32. The solid transdermal therapeutic systemas defined in claim 25, wherein said separating layer (5) has a layerthickness of from 4 to 23 μm.
 33. The solid transdermal therapeuticsystem as defined in claim 32, wherein said layer thickness is from 4 to10 μm.
 34. The solid transdermal therapeutic system as defined in claim25, wherein said at least one active ingredient-containing matrix (2)contains an active pharmaceutical ingredient and said separating layer(5) is impermeable to said active pharmaceutical ingredient andimpermeable to said UV absorber.
 35. The solid transdermal therapeuticsystem as defined in claim 25, wherein said separating layer (5)consists of a barrier polymer and said barrier polymer is polyethyleneterephthalate, polyacrylonitrile, polyvinyl chloride, polyvinylidenechloride, or a copolymer or co-laminate thereof.
 36. The solidtransdermal therapeutic system as defined in claim 25, wherein said atleast one active ingredient-containing matrix (2) contains an activepharmaceutical ingredient, said backing layer (1) is permeable to saidactive pharmaceutical ingredient and said backing layer (1) consists ofpolypropylene, polyethylene, polyurethane, ethylene-vinyl acetatecopolymer, or a multilayer composite of the foregoing polymers with oneanother.
 37. The solid transdermal therapeutic system as defined inclaim 25, wherein said UV absorber is colorless or yellow.
 38. The solidtransdermal therapeutic system as defined in claim 25, containing anactive pharmaceutical ingredient and wherein said active pharmaceuticalingredient comprises at least one hormone.
 39. The solid transdermaltherapeutic system as defined in claim 38, wherein said activepharmaceutical ingredient is a progestogen.
 40. The solid transdermaltherapeutic system as defined in claim 39, wherein said progestogen isgestodene or levonorgestrel.
 41. The solid transdermal therapeuticsystem as defined in claim 39, which is effective as a fertilitycontrolling preparation.
 42. The solid transdermal therapeutic system asdefined in 38, wherein said active pharmaceutical ingredient comprises aprogestogen and an estrogen.
 43. The solid transdermal therapeuticsystem as defined in claim 42, which is effective as a fertilitycontrolling preparation.
 44. The solid transdermal therapeutic system asdefined in claim 25, containing an active pharmaceutical ingredient andwithout a membrane controlling release of the active pharmaceuticalingredient.
 45. The solid transdermal therapeutic system as defined inclaim 25, wherein said separating layer comprises a polyethyleneterephthalate.
 46. The solid transdermal therapeutic system as definedin claim 25, wherein said backing layer comprises a polyethylene.
 47. Asolid transdermal therapeutic system (TTS) with a UV absorber, saidsolid transdermal therapeutic system comprising a sequence of at leastfive layers; wherein said at least five layers comprise a backing layer(1), an adhesive layer (4), a separating layer (5), at least one activeingredient-containing matrix (2), and a detachable protective film (3);wherein the adhesive layer (4) is between the backing layer (1) and theseparating layer (5), the separating layer (5) is between the adhesivelayer (4) and the at least one active ingredient-containing matrix (2),and the at least one active ingredient-containing matrix (2) is betweenthe separating layer (5) and the detachable protective film (3); whereinsaid UV absorber consists of2,4-bis-([4-(2′-ethylhexyloxy)-2-hydroxy]phenyl)-6-(4-methoxyphenyl)-(1,3,5)-triazineas the sole UV absorber in the system, said UV absorber is present in aconcentration of from 0.5 to 4.0% (m/m) in dissolved form in theadhesive layer and said UV absorber is also optionally present in thebacking layer (1); and wherein the solid transdermal therapeutic systemis transparent; and wherein the active ingredient comprises gestodeneand ethinyl estradiol.
 48. The solid transdermal therapeutic system asdefined in claim 47, wherein the at least one activeingredient-containing matrix (2) has a weight per unit area of from 30to 150 g/m².
 49. The solid transdermal therapeutic system as defined inclaim 47, wherein the weight per unit area of the at least one activeingredient-containing matrix (2) is from 50 to 120 g/m².
 50. The solidtransdermal therapeutic system as defined in claim 47, wherein theadhesive layer (4) has a weight per unit area of from 5 to 50 g/m². 51.The solid transdermal therapeutic system as defined in claim 50, whereinthe weight per unit area of the adhesive layer (4) is from 20 to 30g/m².
 52. The solid transdermal therapeutic system as defined in claim47, wherein said UV absorber is present in a concentration of from 0.5to 2.5% (m/m) in dissolved form in the adhesive layer (4).
 53. The solidtransdermal therapeutic system as defined in claim 47, wherein said UVabsorber is present in the adhesive layer (4).
 54. The solid transdermaltherapeutic system as defined in claim 47, wherein the at least oneactive ingredient-containing matrix (2) and the adhesive layer (4) areself-adhesive and comprise at least one polyisobutylene polymer.
 55. Thesolid transdermal therapeutic system as defined in claim 47, whereinsaid separating layer (5) has a layer thickness of from 4 to 23 μm. 56.The solid transdermal therapeutic system as defined in claim 55, whereinsaid layer thickness is from 4 to 10 μm.
 57. The solid transdermaltherapeutic system as defined in claim 47, wherein said at least oneactive ingredient-containing matrix (2) contains the activepharmaceutical ingredient and said separating layer (5) is impermeableto said active pharmaceutical ingredient and impermeable to said UVabsorber.
 58. The solid transdermal therapeutic system as defined inclaim 47, wherein said separating layer (5) comprises a polyethyleneterephthalate barrier polymer.
 59. The solid transdermal therapeuticsystem as defined in claim 47, wherein said UV absorber is colorless oryellow.
 60. The solid transdermal therapeutic system as defined in claim47, which is effective as a fertility controlling preparation.
 61. Thesolid transdermal therapeutic system as defined in claim 47, whereinsaid backing layer comprises a polyethylene.
 62. The solid transdermaltherapeutic system as defined in claim 25, wherein the at least oneactive ingredient-containing matrix (2) and the adhesive layer (4) areself-adhesive and comprise at least one polyisobutylene polymer.
 63. Thesolid transdermal therapeutic system as defined in claim 25, whereinsaid UV absorber is present in a concentration of from 0.5 to 2.5% (m/m)in dissolved form in the adhesive layer (4).